ALV-J inhibits autophagy through the GADD45β/MEKK4/P38MAPK signaling pathway and mediates apoptosis following autophagy
ALV-J inhibits autophagy through the GADD45β/MEKK4/P38MAPK signaling pathway and mediates apoptosis following autophagy
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ALV-J 通过 GADD45β/MEKK4/P38MAPK 信号通路抑制自噬并介导自噬后的细胞凋亡
DOI：
10.1038/s41419-020-02841-y
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发表时间：
2020-08-12
影响因子：
9
通讯作者：
Xie, Qingmei
中科院分区：
文献类型：
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作者：
Liao, Zhihong;Zhang, Xinheng;Xie, Qingmei
自噬和凋亡是宿主免疫的重要过程，通常被病毒利用以促进其存活。然而，据我们所知，很少有研究病毒感染后自噬和凋亡信号通路的作用机制。因此，本研究的目的是探讨ALV-J感染和GADD 45 β过表达对自噬的抑制作用及其机制。ALV-J感染和GADD 45 β过表达均能抑制自噬，使自噬体不能与溶酶体结合，导致自噬流不完全。值得注意的是，发现GADD 45 β与DF-1细胞中的MEKK 4相互作用。利用小干扰RNA基因敲低GADD 45 β和MEKK 4影响ALV-J感染，提示ALV-J可能通过促进GADD 45 β与MEKK 4结合，激活p38 MAPK信号通路，从而抑制自噬。此外，ALV-J被揭示影响自噬途径之前，影响凋亡途径。综上所述，本研究首次探讨了ALV-J感染对自噬和凋亡的联合作用，并提示ALV-J通过GADD 45 β/MEKK 4/p38 MAPK信号通路抑制自噬。
Autophagy and apoptosis, which are important processes for host immunity, are commonly exploited by viruses to facilitate their survival. However, to the best of our knowledge, very few studies have researched the mechanisms of action of the autophagic and apoptotic signaling pathways following viral infection. Thus, the present study aimed to investigate the mechanisms of action of growth arrest and DNA-damage-inducible β (GADD45β), an important resistance gene involved in the host resistance to ALV-J. Both ALV-J infection and the overexpression of GADD45β inhibited autophagy during the early stages, which prevented the autophagosomes from binding to the lysosomes and resulted in an incomplete autophagic flux. Notably, GADD45β was discovered to interact with MEKK4 in DF-1 cells. The genetic knockdown of GADD45β and MEKK4 using small interfering RNA-affected ALV-J infection, which suggested that ALV-J may promote the binding of GADD45β to MEKK4 to activate the p38MAPK signaling pathway, which subsequently inhibits autophagy. Furthermore, ALV-J was revealed to affect the autophagic pathway prior to affecting the apoptotic pathway. In conclusion, to the best of our knowledge, the present study was the first to investigate the combined effects of ALV-J infection on autophagy and apoptosis, and to suggest that ALV-J inhibits autophagy via the GADD45β/MEKK4/p38MAPK signaling pathway.